Cures to diseases lie in
cells and genes
on stem cells, medicinal chemistry and genetics offers great hope
for those who suffer from a broad range of diseasesfrom
diabetes and stroke, to leukemia and Alzheimers. Scientists
at U.Va. are at the forefront of this work.
by Charlie Feigenoff
WHEN HEALING IS IN THE BLOOD CELLS
they were first introduced over three decades ago, bone marrow
transplants marked a dramatic advance in the treatment of leukemia
and other cancers of the circulatory system. It is a truly audacious
strategy. The blood-producing cells in the marrow of a cancer
patient are completely destroyed by chemotherapy and radiation
and then are replaced with bone marrow cells from other donors
or from specially treated cells from the patients themselves.
long-term prospects for the majority of patients who undergo bone
marrow transplantation are good, but until their bone marrow is
fully regenerated they must be monitored carefully. Because their
white blood cell count is initially so low, they are extremely
susceptible to infection, a danger that is intensified because
their immune system in many cases is deliberately suppressed to
prevent them from rejecting the donor marrow.
have discovered a growth factor that speeds recovery of white
blood cells, but the problem of speeding platelet recovery has
resisted satisfactory resolution. As Dr. Adam Goldfarb notes,
a growth factor to stimulate platelet production has been identified,
but it only works in instances where the bone marrow has not been
completely destroyed. As a result, most cancer patients must undergo
a series of platelet transfusions, a therapy which only provides
are created by bone marrow cells called megakaryocytes. Rather
than increase the rate at which each megakaryocyte generates platelets,
Goldfarb, an associate professor of pathology, is concentrating
on increasing the number of them. He is doing this by taking a
step back into their developmental history to learn more about
their progenitor cell, the BFU-E/Meg. This adult stem cell can
give rise to red blood cells or megakaryocytes. We are trying
to determine the essential regulatory factors that lead this cell
to the megakaryocyte pathway, Goldfarb says. This
will help us develop a target for drug development.
A MATTER OF TIMING
years ago when she was a postdoctoral fellow, associate professor
of neuroscience Heidi Scrable found herself drawn to one of the
fundamental puzzles of cancer research: why a defect in the p53
gene is responsible for so many different kinds of cancer.
p53 gene produces a protein that helps give cells with damaged
DNA time to repair themselves before they divide. People who inherit
a faulty version of the p53 gene have an elevated risk of developing
cancer because these damaged cells begin to accumulate.
and her colleagues believed that timing was a key variable. They
hypothesized that when the mutant version of p53 is activated
while new bone cells are being produced, the result is bone cancer.
If it is turned on when breast tissue is being replenished, the
result is breast cancer.
test her theory, Scrable needed a way to turn genes on and off
at specific timesand in 1990, there was simply no way to
accomplish this. But just last year, she and her colleagues perfected
a system that investigators can use to regulate when and for how
long virtually any gene is expressed.
has turned to the simple, well-known mechanism that bacteria use
to metabolize lactose, a sugar that is found in milk and other
sources. Bacteria have evolved an energy-efficient strategy to
create lactose-digesting enzymes only when they are needed.
normal conditions, a protein repressor binds to a segment of DNA
and turns off the genes that encode enzymes to digest lactose.
When lactose appears in the environment, it renders this protein
repressor ineffective and the genes turn on. Scrable's challenge
was to translate this genetic switch into one that would work
in a laboratory mouse. If she succeeded, she would be able to
control the timing of gene expression simply by feeding mice lactose-like
was an elegant idea but one that proved difficult to realize.
The DNAs of bacteria and mammals use the same four chemical letters
to spell out the steps needed to produce a protein, but the way
they use these letters differs substantially.
found that literally translating the DNA sequence for the lactose
repressor protein from bacteria to mouse did not work. Mammals
are exponentially more complex than bacteria and their genetic
systems are much more complicated. In doing the re-encoding,
we inadvertently introduced sequences that had an adverse effect
on function, she observes.
eight years of trouble-shooting, Scrable created a proof of concept:
a transgenic mouse that can change its pigmentation when this
lactose-activated switch is turned on. Under normal circumstances,
it appears albino. Given lactose in its drinking water, the mouse
turns brown. Feed it pure water, and it turns white again.
system provides researchers with a tight, reversible way to control
gene expression in mammals that can be applied to a variety of
experimental situations and help us understand the temporal dimensions
of genetic diseases. Among other uses, this system gives
us the ability to determine if timing of gene expression affects
the kinds of tumors that appear in people with the mutant version
of p53, she says. We can also find out if these effects
can be suppressed or even reversed if the gene is turned off at
the right time.
TEST DRIVING STEM CELLS
years ago, the automobile was a mechanical marvel, but it didn't
really gain acceptance until there was a support infrastructure
in place that included roads, bridges and gas stations. The same
thing could be said for stem cells today. Inducing adult stem
cells to transform themselves into specific types of tissue is
a remarkable scientific breakthrough, but it is not enough in
itself to yield new therapies. That's why work by researchers
like Roy Ogle is so important. Ogle is creating the infrastructure
needed to harness stem cells to heal bone fractures and regenerate
taps all the techniques of tissue engineering. For instance, in
an effort to regenerate sciatic nerves, he is trying out a variety
of adult stem cells. These include those extracted from fat tissue
as well as stem cells he and M.D./Ph.D. student Sunil Tholpady
have identified in the lining of the brain and spinal cord. In
addition, he is exploring the different kinds of materials that
can be used to create a matrix to hold and organize these cells.
Ogle is also experimenting with combinations of growth factors
and other substances needed to induce adult stem cells to follow
a desired developmental path.
cell research has led to the most exciting advances in biomedical
discovery that I have witnessed. I can't think of a disease or
a disorder that doesn't lend itself to stem cell intervention.
and his colleagues have found that each line of adult stem cells
has an inherent phenotype. In effect, it is prone to be converted
to one particular cell type rather than another. For example,
adult stem cells derived from fat can be converted to nerve cells
in just 24 hours, while it takes two weeks to convert them into
bone and cartilage and even longer to induce them to become muscle
cells, he found.
is a limitation in comparison with embryonic stem cells, which
are more readily plastic and easily converted to a wide range
of cell types. On the other hand, the limitations of adult stem
cells increase their potential utility in specific cases. If you
are interested in producing high yields of nerve cells, you are
much better starting from a fat stem cell than an embryonic one.
HELP WANTED: A NEW CELL TO PRODUCE INSULIN
you wanted to mix metaphors, you could say that the body's insulin-producing
mechanism is our Achilles heel. Insulin is the hormone that enables
glucose circulating in our blood to enter cells, where it is translated
into energy. In other words, it is absolutely essential for life.
Furthermore, when glucose builds up in the blood, it can lead
to stroke, heart disease, blindness, and nerve damage.
there is only one type of cell in the body capable of producing
insulin: the beta cell. The problem with beta cells is that there
are not very many of them. Thinly spread across the pancreas in
tiny islets, they account for no more than 2 percent of all cells
in that organ and a minute fraction of all cells in the body.
It is the small number of beta cells that makes us vulnerable.
It is all too easy for all of them to be destroyed, as in Type
I diabetes, or to be damaged, as in Type II.
Dr. Raghavendra Mirmira, a promising long-term strategy for treating
diabetes is not to restore a system that is inherently fragile,
but to find a new way of producing insulin within the body. In
other words, he is looking to find a more robust and numerous
replacement for beta cells.
and his colleagues are pursuing this quest on a number of levels.
Broadly speaking, I'm interested in identifying substances
that are found only in beta cells and not in others, he
notes. We then try to determine if these substances regulate
the genes responsible for insulin production and to find out if
these substances can be used to produce insulin in a different
Mirmira is concentrating on two transcription factorsPdx1
and Nkx6.1that play an important role in beta cell insulin
production on the genetic level. Interestingly enough, these transcription
factors bind to different genes in other cells. Mirmira is concentrating
on trying to find out what makes them behave as they do in beta
his work dovetails with the pioneering investigations of chromatin
being carried on by microbiologist David Allis and other researchers
at U.Va. Chromatin is the DNA-protein complex that gives genetic
material its basic structure. In Mirmira's view, it may well be
the structure of the chromatin that differentiates the beta cell
from other cells in the pancreas. If he can find a cell that retains
the capacity to adjust its chromatin structure to match that of
the beta cell, he might be able to induce it to produce insulin.
WHEN FAT CAN BE BENEFICIAL
a country in which 34 percent of the population is overweight
and 27 percent is obese, fat has a deservedly bad reputation.
Research under way by Dr. Adam Katz and his colleagues demonstrates
that fat may have some saving graces. Having fat, though not necessarily
being fat, might one day save your life.
has found a variety of progenitor cells in the stromal cells associated
with fat tissue. Though more differentiated and less plastic than
stem cells found in embryos, these adult stem cells still retain
the capacity to transform themselves into other kinds of tissues.
Katz's goal is to identify molecular and cellular-level differences
among these cells, to assess the limits of their plasticity, and
then tease out the best methods to convert them to desirable cell
types. For instance, heart muscle derived from adult stem cells
could be used to treat patients after a heart attack, while bone
cells could be used to heal complex fractures or to treat osteoporosis.
a gift of $300,000 from former dermatology department chair Dr.
Peyton Weary and his family, Katz is focusing on the use of adult
stem cells found in fat to produce and repair skeletal muscle.
Other projects in his lab involve efforts to regenerate or repair
heart muscle, the central nervous system, and bone cells. He is
collaborating with Drs. Roy Ogle, Kevin Lee, and Brent French
on these efforts.
The adult stem cells that Katz studies have been removed from
patients undergoing liposuction, a cosmetic procedure typically
used to trim waistlines, not save lives.
by Tom Cogill
from the Fall 2002 issue of Explorations